Adverse events associated with intravenous iron infusion (low-molecular-weight iron dextran and iron sucrose): a systematic review

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1 Transfusion Alternatives in Transfusion Medicine TATM Adverse events associated with intravenous iron infusion (low-molecular-weight iron dextran and iron sucrose): a systematic review JULIA CRITCHLEY*, MSc, DPhil & YENAL DUNDAR, MD, MPhil *Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK; Herefordshire Primary Care Unit Trust, The Stonebow Psychiatric Unit, County Hospital, Hereford, UK Correspondence to: Dr Julia Critchley, Institute of Health and Society, Newcastle University, Leech Building, Newcastle upon Tyne, NE2 4HH, UK j.a.critchley@ncl.ac.uk Publication data Received: 26 September 2006 Revision received: 21 December 2006 Accepted: 22 December 2006 Keywords Adverse events Intravenous iron Iron dextran Iron sucrose Systematic review SUMMARY Intravenous iron administration is an effective method of treating iron deficiency anemia, but there have been concerns about adverse side effects, particularly serious events such as anaphylactic reaction. Several different forms of intravenous iron are available, but few studies have attempted to compare the frequency of adverse events. We carried out a systematic review to assess the frequency of adverse drug events (ADEs) associated with (i) low-molecular-weight intravenous iron dextran and (ii) iron sucrose. We searched several electronic databases; two reviewers screened all studies identified and extracted data. We included 60 studies, but few directly compared adverse events associated with two or more forms of iron, and most were not specifically designed to evaluate adverse events. In general, with the exception of high-molecular-weight iron dextran (HMWID), serious or life-threatening adverse events appeared rare. Several studies showed lower risks of ADEs on low-molecular-weight iron dextran (LMWID) compared with HMWID, and one large review found a reduced risk on LMWID compared with iron gluconate. Two studies showed little difference between iron sucrose and iron gluconate, and two further studies had similar rates of adverse drug events between iron sucrose and LMWID; however, the sample size for most of these studies was too small to draw firm conclusions. Adequately powered direct comparisons of different forms of intravenous iron are required to assess the safety profiles. INTRODUCTION Anemia is the leading cause of disability worldwide, 1 and many groups of patients need iron supplementation (e.g. patients in renal failure, those with inflammatory bowel disease, and pregnant women among others). Oral iron supplementation is often poorly tolerated due to gastrointestinal side effects. 2 4 Other problems with oral iron include poor compliance and lack of efficacy. 2,5 Intravenous iron is an alternative for these patients, but 8 Journal Compilation 2007 LMS Group Transfusion Alternatives in Transfusion Medicine doi: /j X x

2 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 9 there have been concerns about side effects associated with forms of intravenous iron used in the past, particularly high-molecular-weight intravenous iron dextran (HMWID trade names include Dexferrum and Imferon). 4,6 7 New forms of intravenous iron are now available including low-molecular-weight intravenous iron dextran (LMWID trade names InFed or CosmoFer), iron sucrose or saccharate (Venofer) and iron gluconate (Ferrlicit). LMWID has a molecular weight of around 90,000 daltons, compared with 265,000 for HMWID. Molecular weight may have an impact on the safety profiles of these products. From selected studies, it has been reported that LMWID dextran offers a safety profile that is very different from the older HMWID complexes. 8 LMWID has a significantly lower risk of both serious and nonserious acute adverse drug events (ADEs) compared with HMWID. 8 However, few studies have attempted to assess all the evidence on the safety profile of these two products, and there is a need to establish whether LMWID has the same side effect profile as the HMWID previously used, and how the side effects of LMWID compare with other forms of intravenous iron. Further, newer intravenous forms, such as iron sucrose, are now available, and updated summaries of their side effects are also needed. This systematic review aims: 1 to identify, appraise and summarize studies comparing the side effect profile of LMWID and iron sucrose with each other and with other forms of intravenous iron such as iron gluconate, and HMWID. 2 to identify, appraise and summarize studies reporting on the side effect profile of LMWID and iron sucrose (i.e. case series of patients receiving iron dextran or iron sucrose, but not comparing safety with other forms of intravenous iron). METHODS Search strategy The search strategy aimed to identify all relevant studies relating to the use of LMWID complex (trade names InFed or CosmoFer) and iron sucrose (trade name Venofer) compared with each other or with HMWID (trade name Dexferrum or Imferon) or iron gluconate (trade name Ferrlecit) see Appendix 1. The electronic databases including MEDLINE, EMBASE, Science Citation Index Expanded/Web of Science and The Cochrane Central Register of Controlled Trials (2004, issue 3) were searched for the period from 1990 to December The search was not limited to any specific study design, had no language restrictions and was conducted without methodological filters. Specific drug terms (e.g. iron dextran, iron sucrose, CosmoFer, InFed and Venofer) were included. Inclusion criteria Randomized controlled trials (RCTs) or other study designs including uncontrolled retrospective/prospective studies were included if they reported on ADEs associated with use of (i) LMWID complex (CosmoFer, InFed), or (ii) iron sucrose or saccharate (Venofer). Case studies with fewer than 10 patients were excluded, as these are too small to obtain reliable data on ADEs. We identified studies reporting solely on the ADEs associated with LMWID complex, or with iron sucrose. We also identified a small number of comparative studies, comparing the frequency of ADEs on LMWID or iron sucrose with each other or with other forms of intravenous iron (iron gluconate and HMWID). RESULTS Description of studies Studies comparing different forms of intravenous iron Ten studies compared ADEs on different forms of intravenous iron (Table 1). Two studies compared iron sucrose (Venofer) with iron gluconate. 9,10 One casecrossover study compared LMWID (InFed) with iron sucrose (Venofer). 11 One other study compared iron dextran with iron sucrose, but it was unclear whether LMWID or HMWID was used. 12 One large chart review (a retrospective method of collecting data that involves reviewing medical records) compared LMWID (InFed) with both HMWID (Dexferrum) and iron gluconate (Ferrlecit). 13 One study 14 compared LMWID (InFed) with iron gluconate (Ferrlecit). Four studies compared LMWID with HMWID. Studies of LMWID A total of 47 references were identified to which the inclusion criteria were applied. Of these, 19 studies met the inclusion criteria (Table 2), including two RCTs,

3 10 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 1. Characteristics and nature of ADEs associated with two or more forms of intravenous iron Intervention/study design and details Nonserious ADEs 1. Iron sucrose compared with iron gluconate Kosch et al RCT among stable Munster, Germany rhepo-treated hemodialysis patients with two groups: (1) IV iron sucrose (Venofer) (n = 27) (2) IV iron gluconate (Ferrlecit) (n = 28) Bulvik et al Department of Haematology, Netanya, Israel Prospective comparative study of 98 IDA patients Group A, n = 57, received Ferrlecit (iron gluconate); Group B, n = 41, received Veneferrum (iron saccharate) 10 infusions, 100 mg over 3 hours. 2. Iron sucrose compared with iron dextran Moniem and Prospective crossover study Bhandari in 39 stable hemodialysis Hull, UK patients. Received fortnightly 100 mg iron sucrose (Venofer), converted to 100 mg fortnightly iron dextran (CosmoFer) for 6 months, then back to Venofer. Patients received 2111 doses Venofer and 2287 doses CosmoFer, respectively. Prakash et al Toronto, Canada Retrospective analysis of 379 patients attending PD clinics over a 5-year period. 33 received iron dextran, 23 iron saccharate, 5 iron dextran and iron saccharate The most common were flu, infections, sinusitis, surgery and pneumonia. Most of the reported ADEs were associated with chronic renal failure, and none considered to be related to the drugs Included nausea, severe diarrhea, metallic taste, moderate hypotension, local phlebitis, severe acute lower back pain, giddiness. No differences between groups. Minor events included flushing/tingling, diarrhea, vomiting, headache, chest pain. Minor reactions included skin rash, myalgia, chest pain, abnormal sensation in chest None 16 ADEs on iron sucrose (over 174 infusions) 14 ADEs on iron gluconate (over 740 injections) (Total incidence of 44% regardless of iron preparation) None Moderate ADEs: Gluconate 4/57* Saccharate 3/41 Minor ADEs: Gluconate 10/57 Saccharate 5/41 None 5/2111 ADEs on Venofer (0.237%, 95% CI 0.077% to 0.55%, 7/2287 ADEs on CosmoFer (0.0031%, 95% CI 0.12% to 0.63%). Iron dextran: 1/34 had anaphylactic reaction (hypotension, bradycardia, vomiting). Iron saccharate: 1/23 anaphylactic reaction Iron dextran: 5/34 (14.7% of patients, 7.4% of injections) had ADE, mostly minor (unclear what form of iron dextran) Iron saccharate: 2/23 (8.7% of patients, 4.3% of injections) had minor ADEs ADEs were similar for both groups. ADEs were similar for both groups. Abstract. Limited methodological details. Includes one patient who had abnormalities of liver function tests No reported major clinical events or anaphylaxis. ADEs were similar for both groups. No deaths, hospitalizations or permanent disabilities. ADEs were similar for both groups.

4 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 11 Intervention/study design and details Nonserious ADEs 3. Iron dextran compared with iron gluconate Chertow et al Review of FDA data, USA LMWID (InFed) vs. LMWID (Dexferrum) vs. sodium ferric gluconate (Ferrlecit) Retrospective review of FDA data on ADEs ( ). All parenteral ironrelated ADEs reported to FDA, Uppsala, Sweden. Total no. of InFed doses administered: 14,919,000 Total no. of Ferrlecit doses: 1,083,000 LMWID (InFed): Allergic reaction: 13 Facial edema: 5 Pruritus: 19 Urticaria: 10 Gluconate (Ferrlecit): Allergic reaction: 7 Facial edema: 1 Pruritus: 10 Urticaria: 5 LMWID (InFed) Nausea: 21 Vomiting: 9 Gluconate (Ferrlecit): Nausea: 15 Vomiting: 9 LMWID (InFed): Back pain: 23 Chest pain: 33 Tachycardia: 10 Hypotension: 35 Dyspnea: 7 Sweating: 9 Gluconate (Ferrlecit): Back pain: 15 Chest pain: 23 Tachycardia: 2 Hypotension: 23 Dyspnea: 18 Sweating: 5 Fletes et al Fresenius Medical Center, USA LMWID (InFed) vs. HMWID (Dexferrum) Retrospective study, all clinical variance reports for drug-related ADEs filed at Fresenius Medical Care, North America facilities October 1998 March 1999 InFed 55 ADEs from 675,024 infusions Dexferrum 110 ADEs LMWID (InFed): Anaphylactic reaction 28/14,919,000 Death 9/14,919,000 Respiratory depression 7/14,919,000 Gluconate (Ferrlecit): Anaphylactic reaction 3/1,083,000 Death 1/1,083,000 Respiratory depression 0/1,083,000 Average ADEs reported per patient: InFed 3.1 per patient Ferrlecit 3.6 per patient Dexferrum 3.0 per patient Total major ADEs significantly increased among recipients of Dexferrum (OR 5.5, 95% CI ) and Ferrlecit (OR 6.2, 95% CI ) compared with InFed. InFed total ADEs: 598/14,919,000, i.e % of infusions experienced ADEs (95% CI = % to %). Ferrlecit total ADEs: 271/1,083,000, i.e % of infusions experienced ADEs (95% CI = 0.022% to 0.028% Dexferrum total ADEs: 1112/5,058,000, i.e. 0.02% (95% CI = 0.021% to 0.023%) Serious ADEs per million doses of 100 mg: InFed 11.6 Ferrlicit 49.6 Dexferrum 57.9 None 55 reported ADEs to InFed out of 675,024 infusions ( ), i.e. = %, 95% CI % to % Significantly higher rates of life-threatening ADEs observed among Dexferrum compared with InFed 8.12-fold increased risk with Dexferrum (95% CI ).

5 12 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 1. Continued Intervention/study design and details Nonserious ADEs Peck et al Philadelphia, USA McCarthy et al Mayo Clinic, USA Case Jackson MS, USA LMWID (InFed) vs. HMWID (Dexferrum) Prospective study. 28 children with irritable bowel disease and Fe deficiency anemia. 51 infusions were given between 1988 and 1998 LMWID vs. HMWID Retrospective review June 1992 July courses of parenteral iron dextran given to 254 patients. 468 of these courses were InFed, the remainder were HMWID. Patients: Male 57% Age > 60 64% Total courses 468 Retrospective review of TDI iron dextran (InFed) and HMWID (Dexferrum) administered to 156 home dialysis patients attending Kidney Care Inc, Jackson, MS, from 1992 to patients received InFed (422 doses) 14 patients received Dexferrum (76 doses) Included cutaneous reactions (itching, flushing, hives, rash), gastrointestinal (nausea, diarrhea, abdominal pain, vomiting) InFed 4 ADEs during 44 (9%) infusions Dexferrum 5 ADEs during 7 (74%) infusions None ADEs per 100 courses 3.2 (i.e. 3.2%, 95% CI 1.8% to 5.2%) Courses with an ADE: 10 (2.1%) InFed 5/142 (i.e. 3.5%, 95% CI 1.2% to 8.0%) patients had any reaction (including itching, urticaria, nausea and vomiting). Dexferrum 4/14 (28.6%, 95% CI 8.4% to 58.1%) of patients had severe reactions including severe back and leg pain, urticaria, and shortness of breath. Nature and severity of ADEs not reported, available as an abstract only. Multivariate analysis compared ADEs on InFed HMWID dextran threefold increase in odds of ADE associated with high-molecularweight ADE (OR = 3.0, 95% CI ). After controlling for gender, age, race, prior drug allergy and diabetes. 95% CI, 95% confidence intervals; ADEs, adverse drug events; FDA, Food and Drug Administration; HMWID, high-molecular-weight iron dextran; IDA, iron deficiency anemia; IV, intravenous; LMWID, low-molecular-weight iron dextran; OR, Odds Ratio; PD, peritoneal dialysis; rhepo, recombinant human erythropoietin; RCT, randomized controlled trial; TDI, total dose infusion.

6 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 13 Table 2. Characteristics and nature of ADEs associated with LMWID Intervention/study design and details Nonserious ADEs Auerbach et al Multicenter RCT, USA Barton et al Birmingham, AL, USA Earley et al John Hopkins School of Medicine, Baltimore, USA Multicenter RCT n = 157 EPO-treated patients with chemotherapy-related anemia No. iron 36 Oral iron 325 mg twice daily 43 Bolus group 100 mg IV 37 TDI group 41 (All patients received iron dextran as InFed) Uncontrolled observational study of iron-deficient patients with normal renal function: No. 135 Male 26/ infusions of IV iron to these 135 patients. Prospective case study of 11 patients receiving IV iron dextran Nausea: Oral iron group 1/43 Arthralgia-myalgia (delayed reactions) Grade I TDI group 2/41 Grade II Bolus group 1/37 Fatigue Bolus group 1/37 Shortness of breath Bolus group 1/37 Flushing 3/135 (2%) Nausea 1/135 (1%) Arthralgias, myalgias, bone aches: 10/135 (7%) Weakness, dizziness 3/135 (2%) Cardiac arrhythmia 1/135 (1%) Metallic taste 1/135 (1%) Swollen eyelid 1/135 (1%) Paresthesias 1/135 (1%) TDI group Death 1/41 (unrelated to study drug) Oral iron group Death 1/43 (unrelated to study drug) Total ADEs: TDI group 3/41 Bolus group 3/37 Total ADEs for InFed therefore 6/78 (i.e. 7.7%, 95% CI = 2.9% to 16.0%). Total ADEs in oral iron group 2.3% (95% CI 0.06% to 12.3%) ADEs did not require discontinuation of therapy. None Mild ADEs: 18/135 (13%, 95% CI 8.1% to 20.3%) 1/11 (reported feeling short of breath after 30 mg of infusion, infusion stopped and patient treated for possible allergic reaction) 1/11 patients experienced a major side effect (i.e. 9.1% of patients, 95% CI 2.3% to 41.3% Two patients received Dexferrum during period when InFed unavailable. Unclear whether ADEs were associated with InFed or Dexferrum, therefore ADEs associated with InFed may be overestimated. There was one acute hypersensitivity reaction, but this appears to be for a patient receiving Dexferrum. States no other major side effects seen, but minor side effects not reported. 95% CI, 95% confidence intervals; ADEs, adverse drug events; EPO, erythropoietin; ESRD, end-stage renal disease; HMWID, high-molecular-weight iron dextran; HPN, home total parenteral nutrition; IBS, inflammatory bowel syndrome; IV, intravenous; LMWID, low-molecular-weight iron dextran; OR, Odds Ratio; RCT, randomized controlled trial; RLS, restless leg syndrome; SC, subcutaneous; TDI, total dose infusion; TSAT, transferring iron saturation percentage.

7 14 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 2. Continued Intervention/study design and details Nonserious ADEs Fishbane et al (data also presented in Schaefer ) USA Henry Pennsylvania Hospital, Philadelphia, USA. Kaufman et al Multicenter, USA Khaodhiar et al USA LMWID InFed Retrospective review of charts (patients from four hemodialysis patients with ESRD All patients included) Patients: No. 573 Male 49% Age (year) 48.6 ± 4.2 Diabetes 30% Retrospective chart review of patients referred over a 2-year period for administration of EPO prior to elective orthopedic surgery. Part of a RCT (but not a randomized comparison). Total 208 Epoetin SC 107 Epoetin IV patients received 3588 doses of iron dextran 100 mg at 10 consecutive dialysis sessions. Patients with TSAT > 20% and serum ferritin > 100 mg/ ml. (InFed) Retrospective case study n 55 (treated with HPN, ) Patients received InFed: 20 Records of 207 HPN patients from January 1994 December 1999, at the Beth Israel Deaconess Medical Center home nutrition support center. Itching 1.5% Skin flushing 0.3% Nausea 0.5% Dyspepsia 0.5% Chest pain 1.0% Hypotension 0.5% Swelling 0.5% Headache 0.3% Myalgias 0.2% Wheezing or dyspnea 1.5% Anaphylactic reaction 10/573 patients Cardiac arrest 0.2% Serious ADEs (led to hospitalization) 4 (0.7% patients) No. of patients discontinued medication due to ADEs 22 (3.8%) Not reported No. of patients with serious ADEs: 2/180 (1.1%, 95% CI 0.13% to 4.0%) Of the patients receiving TDI: Rash 2/13 Urticaria 1/13 (this patient also had shortness of breath) Of the patients receiving TDI: Chest tightness: 1/13 (this patient also had shortness of breath and infusion discontinued) Adverse events: 27 patients had ADEs related to IV iron (i.e. 4.7%, 95% CI 3.1% to 6.8%) Total no. of ADEs = 30 (5.2%). No patient died or developed permanent disability. 3/157 patients (1.9%, 95% CI 0.04% to 5.5%) had any significant, immediate reaction including rash, facial swelling, and chest tightness. All symptoms resolved within 30 minutes. 2/180 (1.1%, 95% CI 0.13% to 4.0%) Only first course of treatment per person included unless patient had a reaction to any course, in which case that course was included. Rates are therefore per person and not per treatment episode. ADEs clearly defined and assessed by two reviewers. Published as abstract only limited methodological details Minor ADEs not reported. 3/13 Reports on ADEs in only a very small sample (n = 13) of patients receiving TDI iron dextran out of 207 patients initially reviewed. 95% CI, 95% confidence intervals; ADEs, adverse drug events; EPO, erythropoietin; ESRD, end-stage renal disease; HMWID, high-molecular-weight iron dextran; HPN, home total parenteral nutrition; IBS, inflammatory bowel syndrome; IV, intravenous; LMWID, low-molecular-weight iron dextran; OR, Odds Ratio; RCT, randomized controlled trial; RLS, restless leg syndrome; SC, subcutaneous; TDI, total dose infusion; TSAT, transferring iron saturation percentage.

8 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 15 Intervention/study design and details Nonserious ADEs Mamula et al Philadelphia, USA Peebles and Pai Sunderland, UK Schaefer New Jersey, USA Sloand et al University of Rochester Dialysis Unit, USA InFed Retrospective review of charts of all pediatric patients with IBS at Children s Hospital of Philadelphia, USA, who received TDI iron ( ) n 70 (Analyzed 34) Sunderland Royal Hospital, renal failure (Hemodialysis unit). Iron-hydroxide dextran (CosmoFer) Retrospective review from January 2002 LMWID ferric hydroxide (InFed) Retrospective review No. unclear Kennedy Dialysis Center, Sewell, New Jersey. January 1997 March test doses of InFed Iron dextran (InFed) vs. placebo (normal saline IV) RCT n 25 (patients with ESRD and RLS at University of Rochester Dialysis Unit). InFed 11 Placebo 14 Male 71% Rash 1 Shortness of breath 10 Muscle spasm 1 Chills 2 Diaphoresis 1 Hypotension 3 Carpal spasm 1 11 allergic reactions recorded (one during TDI and 10 during test dose). One patient had allergic reactions on two separate occasions. None were lifethreatening and none required infusion. Retrospective review many patients excluded (only 34 of 70 included). None None None No adverse effects were observed in > 50 patients ( ) Retrospective review exact denominator not reported. Allergic reaction 1/207 Itching 2/207 (one for outpatients maintenance dosing) Nausea and vomiting 2/11 (placebo 3/14) Headache 2/11 (placebo 0/14) 3 Also used InFed from , three reactions recorded but no denominator reported. No information on severity of allergic reactions reported. Retrospective review 10/11 in iron dextran group had some symptoms (91%, 95% CI 59% to 99%) compared with 8/14 in placebo group (57%, 95% CI = 29% to 82%) Very high incidence of ADEs in both placebo and iron dextran arms, and the difference is not statistically significant (Relative risk = 1.59, 95% CI = 0.97 to 2.84). Most appear to be mild. 95% CI, 95% confidence intervals; ADEs, adverse drug events; EPO, erythropoietin; ESRD, end-stage renal disease; HMWID, high-molecular-weight iron dextran; HPN, home total parenteral nutrition; IBS, inflammatory bowel syndrome; IV, intravenous; LMWID, low-molecular-weight iron dextran; OR, Odds Ratio; RCT, randomized controlled trial; RLS, restless leg syndrome; SC, subcutaneous; TDI, total dose infusion; TSAT, transferring iron saturation percentage.

9 16 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON comparing LMWID with oral iron, placebo, or different methods of delivering intravenous iron. The remaining studies were of observational data (e.g. retrospective case series and reports of ADEs, prospective clinical studies). Seven studies (or eight including Prakash et al. 12 where the form of iron dextran is not specified) compared LMWID with HMWID, iron gluconate or iron sucrose and are detailed in Table 1. Eleven studies simply reported ADEs among case series of patient receiving LMWID and are reported in Table 2. All but three of these studies were conducted in the United States (the remainder were performed in the UK or Canada), and many were exclusively of patients experiencing renal failure including patients undergoing hemodialysis (eight studies). Other groups of patients included cancer patients, patients with diabetes, those unable to tolerate or respond to oral iron, home total parenteral nutrition (HPN) patients and a mixture of patients undergoing intravenous iron infusion. Studies of iron sucrose Sixty-seven potentially relevant studies were identified, of these 43 met inclusion criteria. Most of the studies were from Europe (Spain, Italy, Netherlands, Germany, UK, France, Austria, Switzerland, Sweden, Poland), Canada or the United States. Two studies were carried out in Pakistan, and one in South Africa. Patients were mostly undergoing hemodialysis, but other groups included pregnant women, patients with inflammatory bowel disease, patients undergoing hip replacements, children receiving parenteral nutrition, or patients sensitive to iron dextran. There were ten RCTs; one compared iron sucrose with iron gluconate, 9 the others compared iron sucrose with oral iron or no iron, or iron sucrose in combination with recombinant human erythropoietin (rhepo) compared with iron sucrose alone. The other studies were observational in design, and most were very small (under 100 patients receiving iron sucrose). Two studies 9,10 compared ADEs on iron sucrose with iron gluconate, and two 11,12 with iron dextran. These are reported in Table 1, and the remaining case series of patients on iron sucrose (n = 39) are reported in Table 3. Reporting of adverse events Reporting of adverse events was not consistent and the level of reporting varied across the studies. Some studies reported on all adverse effects whereas others reported treatment-emergent adverse events, which were new events that began after the first dose of active treatment or events that worsened during therapy. These generally include allergic (e.g. flushing, pruritus, urticaria, rash), gastrointestinal (e.g. nausea and vomiting, diarrhea), systemic (e.g. arthralgias, back pain, headache, fever, tachycardia, hypotension), respiratory (e.g. wheezing or dyspnea) and serious or life-threatening adverse events (e.g. death, cardiac arrest, myocardial infarction, anaphylactic reactions, anaphylactic shock and those that led to hospitalization or discontinuation of treatment). Some studies reported mild or total ADEs whereas others were restricted to major or serious ADEs, which limits comparability between studies. We have provided details of these adverse events along with relevant study information in a series of tables; Table 1 describes results from comparative studies, comparing at least two forms of intravenous iron. Table 2 details studies of LMWID and Table 3 iron sucrose. Quality assessment Overall, the methodological quality of the included studies was variable, and some were poor. Most of the studies were retrospective analyses of patient or adverse event databases. In many cases the databases were not designed specifically for assessing the incidence of ADEs and therefore important information was missing in particular most studies reported the number of ADEs per episode of intravenous iron dextran treatment rather than per patient treated. This may underestimate the incidence of ADEs (as most patients will have received several episodes of treatment). Selection bias is also possible those studies which reported and published data on ADEs associated with iron dextran or iron sucrose may have atypical groups of patients (e.g. referral centers and teaching hospitals). Few studies directly compared ADEs associated with iron dextran with other forms of intravenous iron and even those that did may have selection biases (as it is unclear how decisions were made to prescribe one or other form of intravenous iron). A few studies used both HMWID and LMWID (InFed and Dexferrum) and did not separate results by type of iron dextran, which renders their results uninterpretable. None of the studies reported sample size calculations, which may be an indication of insufficient power. Small

10 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 17 Table 3. Characteristics and nature of ADEs associated with iron sucrose Intervention/study design and details Nonserious ADEs Aaronson and Cornell USA Agarwal et al Indiana, USA Aggarwal et al USA Prospective study of tolerability of IS 24 patients received 500 mg IV iron sucrose over 4 hours. Four patients received 100 mg IV iron sucrose. Tolerability of high-dose IV IS determined in predialysis patients receiving either EPO or darbepoetin. RCT (1) IS + placebo (n = 10) (2) IS + N-acetylcysteine (n = 10) Randomized open-label study in patients with CKD by IS given IV 100 mg/5 minutes. Prospective study of 46 patients: 38 patients received two doses each of IV 500 mg IS, eight patients received different no. of infusions In total 46 patients received 97 infusions None None None Abstract only limited methodological details. Diarrhea 2/20 2/20 2/20 One patient had sudden death not related to the study drug (underlying CAD) Unclear what the serious ADEs were. Minor ADEs (including emesis, angina, lumbago, mild rash) reported in four patients. These patients were allergic to antibiotics None 4/38 Letter only limited methodological details

11 18 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 3. Continued Aronoff et al Multicenter, USA Bayoumeu et al Nancy, France Blaustein et al New York, USA Intervention/study design and details Nonserious ADEs Iron deficient patients given IV IS, 100 mg during hemodialysis sessions. Iron-replete patients given IS, 100 mg, over 5 minutes weekly for 10 weeks. 665 patients included. Multicenter open-label dose-ranging safety study Random, prospective, open study involving 50 pregnant patients with anemia. IV Group n = 24 PO Group n = 23 Prospective dose-ranging study IV sucrose 500 mg Infused over 3 hours on two consecutive days (accelerated dosing regimen). n = 107 CKD patients No anaphylactic and allergic reactions reported Constipation 3 Vomiting 3 Diarrhea 1 Dry mouth 1 Nausea 2 Hypotension 3 Dermatitis 1 Dizziness 1 Pruritus 2 None 29 nonserious ADEs reported in 21 patients (per patient incidence of 4.4%, and per exposure incidence of 0.34%). None None None Epigastric discomfort, nausea, vomiting: 1 patient Abdominal cramps, moderate nausea: 1 patient Possible IS-related mild nausea, diarrhea: 1 patient Sensation of upper body heat: 1 patient Diaphoresis: 1 patient None 10 ADEs were observed in five patients. Of these, seven ADEs in two patients were considered drug-related (nausea, vomiting, diarrhea, and light headedness). 1.8% of patients who had ADEs attributed to IS (95% CI 0.23% to 6.6%).

12 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 19 Bodemar et al University Hospital, Linkoping, Sweden Borawski et al Medical University, Bialystok, Poland Breymann et al Zurich, Switzerland Breymann et al Zurich, Switzerland Intervention/study design and details Nonserious ADEs Retrospective analysis of 61 patients with inflammatory bowel disease attending internal medicine clinic over a 3-year period. Iron dose: 1.4 ± 0.5 g. Prospective study of high dose IV sucrose (200 mg daily in 250 ml saline, given over 1-hour median treatment duration 5 days). n = 24 CRF patients Endothelial injury markers studied Randomized study Group 1: rhepo plus IV IS (Venofer at 200 mg) n = 20 Group 2: IS (Venofer) alone, same dose and admin route n = 20 Women with gestational iron-deficiency anemia RCT with three groups Group 1: rhepo plus IV IS (Venofer, 200 mg, daily) n = 20 Group 2: placebo plus IV IS n = 20 Group 3: oral iron alone (daily for 4 days beginning hours postpartum) n = 20 Postpartum women Slight fever and rash: 1 patient (during IV infusion of IS did not reappear in subsequent infusions) None 1 None None None Metallic taste observed in three patients (unclear which group), feeling warm for a few minutes in two patients. Metallic taste in five patients, feeling warm for a few minutes in three patients (unclear which group) None 5 None 8

13 20 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 3. Continued Chandler et al King s College, London Charytan et al Flushing, NY, USA Intervention/study design and details Nonserious ADEs Uncontrolled prospective dose-ranging study 335 iron infusions administered in 249 hemodialysis patients and was conducted four phases: 200 mg (over 2 hours) n = mg (over 2 hours) n = mg (over 2 hours) n = mg (over 2 hours) n = 35 Summary of data from four prospective studies of IV sucrose. 130 hemodialysis patients who are iron dextran and/or sodium ferric gluconate-sensitive IS given 100- or 200-mg doses 8/22 patients in 500 mg group developed dizziness, hypotension and nausea; and the infusion was abandoned. 2/35 patients in 400 mg group developed hypotension, nausea and lower back pain. Severe diarrhea 1 patient Moderate nausea 1 patient Mild taste disturbances 3 patients Moderate vomiting 1 patient Constipation, dry mouth, skin irritation 1 patient Moderate hypotension 1 patient All above 1 patient No ADEs observed with the 200- and 300-mg doses. The incidence of ADEs with the mg doses given over 2 hours seems to be too high to recommend their routine use. None 14 in 8 patients attributed to IS, none of which resulted in discontinuation of therapy. (6.15% of patients experienced ADEs, 95% CI 2.69% to 11.76%).

14 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 21 Charytan et al Multicenter, USA Charytan et al Multicenter, USA Charytan et al Multicenter, USA Intervention/study design and details Nonserious ADEs Randomized study of 102 predialysis CKD patients treated with EPO Safety data were available on 84 patients: Group 1: oral iron n = 41, for 29 days Group 2: Venofer 200 mg 1/week for 5 weeks n = 43 RCT, open-label, 96 patients with CRF Group 1: oral iron n = 48, 325 mg three times a day Group 2: IV IS (Venofer) 200 mg weekly for 5 weeks n = 48 All patients received epoetin (at least 2000 U weekly through day 43). Extended follow-up continued for an additional 3 months, during which both groups were given IS and/or epoetin. Open-label, single arm, prospective, multicenter study in hemodialysis patients undergoing epoetin therapy. Single dosing regimen of 10 doses of 100 mg each, given on consecutive dialysis sessions 76/77 patients completed treatment and were included in the efficacy analysis, all 77 patients were included in the safety analysis. Oral iron: constipation 8, nausea 7, diarrhea 4, (fatigue, hypotension, hypoglycemia, and skin rash 4 events), and other single events Venofer: transient taste disturbances: 4, GI complaints 3, and 5 disparate single events All ADEs related to GI system. Oral iron: 17/48 (35.4%) Venofer: 6/48 (12.5%) Abdominal pain: 1/77 Diarrhea, nausea: 1/77 Constipation: 1/77 Transient minty taste: 1/77 None Oral iron: Total ADEs 26 Patient with ADEs 17 (41.5%) Venofer: Total ADEs 22 Patient with ADEs 7 (16.3%) Abstract only limited methodological details None Abstract only limited methodological details. safety study. None No patient withdrawals or drug discontinuation caused by drug-related ADEs. Two deaths were not drug-related.

15 22 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 3. Continued Cuenca et al Malaga, Spain Dittrich et al Vienna, Austria Edwards Multicenter, USA (5 sites) Gasche et al Multicenter, Austria Intervention/study design and details Nonserious ADEs Prospective pilot study with nonconcurrent control group Group 1: control group of previous series of pertrochanteric hip fracture patients n = 55. Group 2: n = 55, mg IV IS, given preoperatively. Follow-up efficacy study 45 hemodialysis patients were followed over 1 year Low-dose IV iron regimen administered once or twice monthly using 50 mg IV IS Observational study Hemodialysis patients, all had end-stage renal disease. Most receiving rhepo. No inclusion/ exclusion criteria applied! Patient numbers not reported Prospective multicenter open-label study Six infusions of IS 200 mg for 4 weeks n = 103 patients with severe IBS-associated anemia None None None Systemic ADEs occurred in 0.5% of 594 applications (including hypotension, nausea, and flush after one application) Local pain at the injection site was reported during two applications (0.3%). None 0.5% of applications None None None No methodological details and very limited reporting of side effects: no specific inclusion or exclusion criteria stated Exanthema 1/103 Bitter taste 2/103 Hypotension 1/103 None Four events ADEs observed were generally mild and transient

16 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 23 Gasche et al Multicenter, Austria Gombotz et al Graz, Austria Intervention/study design and details Nonserious ADEs Double blind RCT with a subsequent open-label phase in patients with Crohn disease anemia All patients received IV iron saccharate for 16 weeks. Blinded phase: first 8 weeks, patients were randomly assigned to receive EPO n = 20 or placebo n = 20. Open-label phase: second 8 weeks, EPO dose was increased in nonresponders who had received EPO and EPO therapy initiated in nonresponders who had received placebo. Prospective randomized study of 60 preoperative female patients (for primary hip replacement) Group 1: EPO, n = 20 Group 2: ANHD, n = 20 Group 3: PDAB, n = 20 Groups 1 and 2 received rhepo and iron saccharate 100 mg on day 14, and on day 7 before surgery, if needed. Group 3 received oral iron Local burning at the injection site: 3/40 Bitter taste 2/40 Transient fever 2/40 Transient hypotension 2/40 None Six different ADEs observed in 14 patients. None None None Limited methodological details. Unclear whether truly randomized.

17 24 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 3. Continued Hollands USA Hussain et al Karachi, Pakistan Kooistra et al Utrecht, Netherlands Macdougall et al London, UK Intervention/study design and details Nonserious ADEs Retrospective study to evaluate safety and efficacy of 300 mg IV IS. n = 73 CKD patients Review of medical records of all 73 CKD patients who received IS at least once in Prospective study with two groups of hemodialysis patients treated with EPO Group 1: received IV iron saccharate post dialysis (100 mg twice weekly) n = 10 Group 2: oral ferrous sulfate given 200 mg three times daily n = 10 Both groups received rhepo Prospective study 10 stable hemodialysis patients on rhepo received 100 mg iron saccharate (Venofer) in 60 minutes (protocol 1) and 1 week later 100 mg in 6 minutes (protocol 2). Prospective complete case series of hemodialysis patients for 1 year (n = 116). Received weekly IV bolus of 100 mg iron sucrose. Rash 1 Nausea 11 Vomiting 3 Dysgusia 3 (loss of taste) Constipation 2 Hypotension 11 Anxiety 1 Fatigue 1 None 33 events Abstract only, limited details. Some patients experienced these ADEs prior to IS so causality was difficult to determine. None None None Unclear how patients were assigned to the two groups; small sample size. Methods for identifying and recording ADEs not clear Allergic reactions 0/10 Metallic taste 1/10 Hypotensive episodes 0/10 No reactions recorded, although two patients complained of a transient metallic taste. Total of 4564 injections given over 1 year None One patient Small sample size None 0 2/4564

18 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 25 Michaud et al Lille, France Perewusnyk et al Zurich, Switzerland Rohling et al Zurich, Switzerland Silverberg et al Israel Intervention/study design and details Nonserious ADEs Prospective 2-year study of children receiving parenteral nutrition, with iron deficiency anemic, poor tolerance or unresponsive to oral supplementation. 22 children aged 5 months to 17 years received 100 mg iron sucrose (Venofer) in 0.9% saline. Each received a test dose of 25 mg first. Retrospective review of cases from 1992 to patients received 2500 amouples, each containing 100 mg iron. Prospective study comparing (1) oral iron sulfate (n = 6) and (2) IV iron sucrose (Venofer). 200 mg in 250 ml NaCl IV over 20 minutes twice a week (n = 6). Preoperative adults with normal hemoglobin and iron due for elective surgery involving potential blood loss over 500 ml. All patients also received rhepo Unclear retrospective review of 541 patients. 123 predialysis patients received 200 mg IV iron; 360 hemodialysis patients received 100 mg IV iron twice monthly; 200 mg to 58 PD patients weekly. Transient exanthema and mild None 1 1 adverse reaction to test hypotension: 1/22 dose (stopped dose). Rash 4/500 Flush 3/500 Oral: 2/6 None in IV iron group Not clearly stated Side effects were 1.5% relative to total number of patients (95% CI % to 3.0%) and 0.36% relative to number of ampoules. All side effects on first day of treatment. None None (with IV iron) Unclear how patients were assigned to the two groups; small sample size. Not clearly stated None Not clearly stated No anaphylactic reactions in over 20,000 infusions over a 4-year period

19 26 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 3. Continued Stark et al Petah Tikva, Israel Stoves et al Leeds, UK Sunder- Plassman and Horl Vienna, Austria Intervention/study design and details Nonserious ADEs Retrospective review of 136 patients with IDA of different etiology. Retrospective review of patients treated with IV iron sucrose (Venofer) infusions of mg in ml saline over minutes, two to three times a week. Mean no. infusion 10.5 ± 4.2/patient. Total n. infusions RCT among 45 anemia patients with PRI, not yet on dialysis comparing (1) oral iron (ferrous sulfate 200 mg three times a day) n = 23 (2) IV iron sucrose (Venofer) 300 mg monthly, n = 22. Patients followed for average 5.2 months; mean of 0.91 (95% CI 0.84 to 0.98) infusion of iron sucrose per patient per month. Dosing study with four regimens of IV iron saccharate (Ferrivenin) 10, 20, 40 and 100 mg (n = 18 regular hemodialysis patients with renal failure 1/136 moderately severe rash 1/136 headache and dizziness. IV iron: 3/22 possible allergic reactions (including urticarial rash, abdominal pain, arthralgia, myalgia, nausea, headache, paresthesia and loss of consciousness) Oral iron: 1/23 (severe constipation) None 28 (20.6%, 95% CI 14.13% to 28.36%) of patients reported 32 ADEs (1.4% of infusions); in most cases only during first infusion Abstract only limited methodological details None 3/22 All possible ADEs in women with low body mass. Oral iron discontinued in 1/23 patients None None None No clearly described methods for identifying and recording ADEs, although primary aim was to carry out a safety study.

20 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 27 Sunder- Plassman and Horl Vienna, Austria Surico et al Bari, Italy Van Wyck et al US Intervention/study design and details Nonserious ADEs Prospective case series of ESRD patients receiving 100-mg iron saccharate (64 chronically uremic patients undergoing regular hemodialysis). 3/64 chest pain, loin pain or bronchospasm Prospective study in children comparing (1) IV iron saccharate (2- hour infusion in saline, average dose 28 mg/kg, over average 6.5 days, n = 19) (2) IM iron injection (n = 14) Prospective study of 23 patients sensitive to iron dextran; 223 doses in total. Patients received 100-mg IV iron sucrose (Venofer) in 10 consecutive dialysis treatment sessions. Two groups: (1) with mild reactions to iron dextran; received 100 mg IV iron sucrose by IV push over 5 minutes (2) with severe reactions to iron dextran; received same dose or IUV 100 mg in 0.9% NaCl over minutes. IV group: 1/19 (mild systemic reaction), withdrawn Four patients developed pruritus, in one patient thought related to IV iron sucrose, one patient developed metallic taste Symptoms only observed when 100-mg IV iron saccharate injected in under 5 minutes; not observed with slow injection or dose reduction. None 1/19 Not clear how children were assigned to each group. No serious ADEs, episodes of anaphylaxis, patient withdrawals or drug discontinuation. Three ADEs possibly related to IV iron sucrose observed in two patients; these were mild. Primary outcome was safety; reports clearly methods for identifying and recording ADEs.

21 28 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON Table 3. Continued Intervention/study design and details Nonserious ADEs Vychytil and Haag-Weber Location unclear Wali et al Karachi, Pakistan Weisbach et al Nuremberg, Germany Case series of peritoneal dialysis patients treated with 100 or 200 mg of iron saccharate monthly for 6 months, n = 17 Prospective quasirandomized study n = 60, pregnant women, gestation age weeks, with irondeficiency anemia. IV iron sucrose 500 mg = 15 IV iron sucrose 200 mg = 20 IM iron sorbitol = 25 RCT in adult patients schedules for ABD before major orthopedic or cardiovascular surgery. n = 90 Oral iron: 30 IV iron sucrose: 30 No iron: 30 Not clearly described None Side effects occurred in 0.9% after application of 100 mg and 5.9% after infection of 200 mg iron saccharate IV group: 1/35 with moderate abdominal pain, 2/35 with shivering and weakness, 3/35 with phlebitis IM group: 5/25 dropped out due to intolerance (mostly pain at injection site) IV group: general discomfort and dizziness: 1/30, small itching erythema (1/30) Oral group: constipation and diarrhea (7/30), abdominal pain (1/30), itching erythema (1/30) Two patients removed from both oral iron and IV iron group due to mild ADEs. No methodological details and very limited reporting of side effects; most of article reviews other studies and details found only in abstract None Limited methodological details; unclear whether truly randomized None Two patients withdrew from both groups Limited methodological details regarding how patients were randomized/allocation concealed. 90 of 123 patients completed study. 95% CI, 95% confidence intervals; ABD, autologous blood donation; ADEs, adverse drug events; ANHD, acute concomitant normovolemic hemodilution; CAD, coronary artery disease; CKD, chronic kidney disease; CRF, chronic renal failure; EPO, erythropoietin; ESRD, end-stage renal disease; GI, gastrointestinal; HMWID, high-molecular-weight iron dextran; IBS, inflammatory bowel syndrome; IDA, iron deficiency anemia; IM, intramuscular; IS, iron sucrose; IV, intravenous; LMWID, low-molecular-weight iron dextran; OR, Odds Ratio; PDAB, predeposit of autologous blood; PO, per oral; PRI, progressive renal insufficiency; rhepo, recombinant human erythropoietin; RCT, randomized controlled trial.

22 CRITCHLEY & DUNDAR ADVERSE EVENTS ASSOCIATED WITH INTRAVENOUS IRON 29 sample sizes and possibly selected populations mean it is difficult to estimate with confidence or precision the incidence of side effects associated with LMWID in different patient groups. Data analysis We present the results narratively in Tables 1 3. Where feasible and where the denominator was > 50, we calculated the percentage experiencing any ADE and 95% confidence intervals (CI) for this percentage. We have not carried out any statistical pooling (metaanalysis) of adverse events across studies. As the studies are so heterogenous in terms of design, patient groups, definitions and methods of assessing adverse events, it would be inappropriate to combine estimates of the incidence of adverse events across studies. It may be possible in future analyses to combine studies by obtaining individual patient data and hence carry out more detailed data checking and quality assessment, applying consistent inclusion criteria to ensure more robust conclusions. Comparison of ADEs on different forms of intravenous iron Five studies consistently found much lower risks of ADEs on LMWID compared with HMWID. 13,15 18 Two studies compared ADEs on LMWID with iron gluconate (Ferrlecit). One of these found no difference in ADEs, but only four patients received iron gluconate. 14 One large review for the Food and Drug Administration (FDA) 13 found a much higher rate of ADEs for patients receiving iron gluconate (Ferrlecit) compared with LMWID (InFed) (Odds Ratio 6.2, 95% CI ). This finding needs to be replicated in other studies. Two studies compared iron sucrose (Venofer) with iron gluconate (Ferrlicit). 9,10 Neither found any major ADEs, or any difference in ADEs between the two forms of intravenous iron, but the sample size was small in both cases (only 98 and 57 patients respectively). Two studies compared iron sucrose with iron dextran, 11,12 but only one specified the form of iron dextran used (LMWID in Moniem and Bhandari 11 ). Moniem compared the two forms of intravenous iron in a case-crossover design. There were no major ADEs including anaphylaxis, and no difference in ADEs between the two arms; however, only 39 patients were enrolled in this study. Prakash et al. 12 noted one case of anaphylaxis in each group and slightly more mild ADEs in patients administered iron dextran compared with iron sucrose. However, this difference was not statistically significant, the sample size was small, and the type of iron dextran unclear. Adverse events associated with LMWID Over 2000 patients appear to have received LMWID in studies (the exact number is not certain as some studies report only the number of infusions, rather than the number of patients). However, the study by Chertow et al. 13 reviewed an estimated 14.9 million doses of LMWID administered over the 2-year period presumably a far larger number of patients. The frequency of reporting of any ADE associated with LMWID varied greatly between the studies, from about 0.004% to 91%. This range may reflect clinical heterogeneity (different patient groups), chance (as sample sizes were often small), and different definitions of an ADE. In particular, some studies may not have reported milder ADEs comprehensively. It may also reflect publication bias it is plausible that retrospective case series of patients may be more likely to be published if they report a high incidence of ADEs. For this reason, studies with larger sample sizes are likely to provide less biased estimates (as studies with larger sample sizes are more likely to be published regardless of their results). In larger studies where the denominator was infusions rather than patients, ADEs appeared to be less common (although the range of estimates was still vast from approximately 0.004%, 95% CI % to % to 20.5%, 95% CI 9.3% to 36.5%). In studies where ADEs were reported per patient they were more common, as would be expected (ranging from approximately none to 91%, 95% CI 59% to 99%), Sloand s RCT 30 found the highest incidence, but this was in a small study of dialysis patients, ADEs appeared mild and were also very common in the placebo arm of the study), suggesting that they may not necessarily be due to the medication. There were relatively few serious or life-threatening ADEs. Eight of the 19 studies reported that serious ADEs had occurred (although some others did not state clearly whether ADEs were mild or serious). Auerbach et al. s 19 RCT reported one death among 78 patients (but this was